1. We measured interferon and interferon stimulated gene production in response to cellular infection of different viruses in order to gain an understanding of the different signaling modulators that are activated when certain interferon subtypes are induced. We then tested the functional relevance of these results in both cell lines and primary cells. 2. We examined the role of IFIT3 in the antiviral response by studying the effect of IFIT3 overexpression on virus titers of VSV (vesicular stomatitis virus), EMCV (encephalomyocarditis virus) and DV (Dengue virus). Our data show that presence of IFIT3 leads to a decrease in virus titers. Although the precise mechanism is still unknown, IFIT3 demonstrated a clear antiviral effect against several different viruses. 3. Enhancement of the antiviral activity of IFN-alpha2 by Ribavirin: Combination treatments of interferon and ribavirin are successful in treating viral infections, however the mechanism of action for how these agents work together remains unclear. To examine this, we utilized vesicular stomatitis virus (VSV) infection on A549 human lung epithelial cells as an experimental model. Treating cells with ribavirin alone or in combination with interferon resulted in a 4-log10 decrease in VSV titer at 24h compared to untreated cells. We found increased and prolonged activation of pSTAT1 and pSTAT2, and in increases in total STAT1, STAT2, and IRF9 protein expression compared to interferon alone. In addition, expression of the Interferon Stimulated Genes (ISGs) MxA, IFIT3, PKR, and ISG15 showed enhanced expression in the presence of ribavirin alone or in combination with interferon when compared to interferon alone. The increases in pSTAT1 and pSTAT2 activation as well as ISG expression were not present in uninfected cells, suggesting that the enhanced activity induced by RBV required an active viral infection. This prolonged and enhanced activity of interferon signaling and induction of gene expression may play a role in how interferon and ribavirin work together to treat viral infections.